Glaucoma is a leading cause of irreversible blindness and characterized by progressive damage of retinal ganglion cells (RGCs). Growing evidences have linked impaired mitophagy with neurodegenerative diseases, while the E3 ubiquitin ligase parkin may play a key role. However, the pathophysiological relationship between parkin and glaucoma remains largely unknown. Using chronic hypertensive glaucoma rats induced by translimbal laser photocoagulation, we show here that the protein level of parkin and its downstream optineurin proteins were increased in hypertensive retinas. The ratio of LC3-II to LC3-I, the number of mitophagosomes, and unhealthy mitochondria were increased in hypertensive optic nerves. Overexpression of parkin by viral vectors increased RGC survival in glaucomatous rats in vivo and under excitotoxicity in vitro. It also promoted optineurin expression and improved mitochondrial health. In parkin-overexpressed glaucomatous rats, the ratio of LC3-II to LC3-I, LAMP1 level, and the number of mitophagosomes in optic nerve were decreased at 3 days, yet increased at 2 weeks following intraocular pressure (IOP) elevation. These findings demonstrate that dysfunction of mitophagy exist in RGCs of glaucomatous rats. Overexpression of parkin exerted a significant protective effect on RGCs and partially restored dysfunction of mitophagy in response to cumulative IOP elevation.
Glaucoma is a neurodegenerative disease that features progressive loss of retinal ganglion cells (RGCs). Increasing evidences have revealed that impaired mitochondrial dynamics occurs early in neurodegenerative diseases. Optic Atrophy Type 1 (OPA1), a mitochondrial fusion protein, has recently been suggested to be a mitophagic factor. Our previous studies found that glaucomatous retinal damage may be ameliorated by an increase in mitochondrial OPA1. In this study, we explored the mechanism involved in OPA1 mediated neuroprotection and its relationship with parkin dependent mitophagy in experimental glaucoma models. Our data showed that overexpression of OPA1 by viral vectors protected against RGC loss, attenuated Bax expression, and improved mitochondrial health and mitochondrial surface area. Parkin expression and the number of mitophagosomes were upregulated in OPA1 overexpressed RGCs under glutamate excitotoxicity. While knockdown of OPA1 by siRNA decreased protein expression of parkin in RGCs under glutamate excitotoxicity. Two weeks after intraocular pressure (IOP) elevation, the LC3-II/I ratio and the LAMP1 expression were increased in OPA1 overexpressed optic nerve. These findings suggest that OPA1 overexpression may protect RGCs by ways of enhancing mitochondria fusion and parkin mediated mitophagy. Interventions to promote mitochondrial fusion and mitophagy may provide a useful strategy to battle against glaucomatous RGC loss.
Metal-free antiferroelectric materials are holding a promise for energy storage application, owing to their unique merits of wearability, environmental friendliness, and structure tunability. Despite receiving great interests, metal-free antiferroelectrics are quite limited and it is a challenge to acquire new soft antiferroelectric candidates. Here, we have successfully exploited binary CMBrxI1-x and CMBrxCl1-x solid solution as single crystals (0 ≤ x ≤ 1, where CM is cyclohexylmethylammonium). A molecule-level modification can effectively enhance Curie temperature. Emphatically, the binary CM-chloride salt shows the highest antiferroelectric-to-paraelectric Curie temperature of ~453 K among the known molecular antiferroelectrics. Its characteristic double electrical hysteresis loops provide a large electric polarization up to ~11.4 μC/cm2, which endows notable energy storage behaviors. To our best knowledge, this work provides an effective solid-solution methodology to the targeted design of new metal-free antiferroelectric candidates toward biocompatible energy storage devices.
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